Pancreatic cancer is now the fourth leading cause of death from cancer in women and men in the United States. New, innovative approaches to the prevention and treatment of pancreatic cancer are sorely needed. This Program Project Grant (P01) application in pancreatic cancer takes up that challenging need, building on a strong foundation of interest and expertise in pancreatic cancer and in drug development at the Arizona Cancer Center (AZCC) at the University of Arizona. The central theme and goal of this P01 is to speed delivery into the clinic of new therapeutic agents against new targets in pancreatic cancer. The goal of this P01 is that in each year of this P01, we will deliver a new agent into clinical trials in patients with pancreatic cancer, which hits a target discovered and validated in one of the projects of this P01. This P01 application represents a revised application that we feel is an improved, more focused effort against the disease. Responses to each of the critiques are presented in the beginning of each section of the application. Two years ago, the AZCC formed the Sydney Salmon Pancreatic Cancer Team (named after the founding director of the AZCC who passed away from the disease). The team has built an infrastructure of investigators (established and new, in basic, translational, and clinical research), developed a patient base, begun a series of clinical trials, and created an ongoing forum for communicating new research initiatives and findings. In addition, Dr. .Von Hoff, the principal investigator for this application, has stepped down from the Directorship of the Arizona Cancer Center to devote full time to this effort. Our approach to make a difference against pancreatic cancer focuses on the development of innovative, translational ways to tackle the disease. Out of that groundwork effort comes this P01 application focusing on pancreatic cancer. As we hope the reviewers will see, our team has already made substantial progress in identifying new targets in and indeed new approaches to pancreatic cancer. This P01 application focuses that ongoing work and translates that work into new therapeutics that will be brought into patients. This P01 contains three translational research projects whose collective aims are to develop new therapeutics for patients with pancreatic cancer. These related Projects include: (1) Treatment of Hypoxia Resistance in Pancreatic Cancer;(2) Method to Eliminate Pancreatic Cells with Specific Patterns of Mutations/Deletions;and (3) Validation of Amplified Genes in Pancreatic Cancer: New sensitizing Targets for Improved Gemcitabine Therapy. Each project already has some leads and each project is designed to maximize translational potential. As will be seen in the application, the Projects are highly integrated so there is the highest probability we can bring that one therapeutic to the clinic each year. The projects are supported by four highly-integrated shared services (cores): (1) Pancreatic Cancer Biospecimens Repository;(2) Pattern Analysis and Computational Biology Core;(3) Drug Development Core;and (4) Evaluation and Administration Core. These cores provide material, informatic, development and administrative support for the projects. Since we are blessed by having such excellent shared services at the Arizona Cancer Center (AZCC), the cores in this proposed P01 are designed to utilize those cores and therefore for this application we are only asking for resources to provide the services that are over an above the services that can be provided by these AZCC cores. In addition, both internal and external scientific advisory boards are included in the P01 to assure maximum input into the science and into the execution of the Projects. The overall goal of this P01 is the delivery into the clinic one new therapeutic agent against a new target in pancreatic cancer each year of the P01. We feel this effort, with new approaches to pancreatic cancer, concentrated in a P01, has a chance to make an impact on the disease.